\\n\\n
Dr. Pletser’s experience includes 30 years of working with the European Space Agency as a Senior Physicist/Engineer and coordinating their parabolic flight campaigns, and he is the Guinness World Record holder for the most number of aircraft flown (12) in parabolas, personally logging more than 7,300 parabolas.
\\n\\nSeeing the 5,000th book published makes us at the same time proud, happy, humble, and grateful. This is a great opportunity to stop and celebrate what we have done so far, but is also an opportunity to engage even more, grow, and succeed. It wouldn't be possible to get here without the synergy of team members’ hard work and authors and editors who devote time and their expertise into Open Access book publishing with us.
\\n\\nOver these years, we have gone from pioneering the scientific Open Access book publishing field to being the world’s largest Open Access book publisher. Nonetheless, our vision has remained the same: to meet the challenges of making relevant knowledge available to the worldwide community under the Open Access model.
\\n\\nWe are excited about the present, and we look forward to sharing many more successes in the future.
\\n\\nThank you all for being part of the journey. 5,000 times thank you!
\\n\\nNow with 5,000 titles available Open Access, which one will you read next?
\\n\\nRead, share and download for free: https://www.intechopen.com/books
\\n\\n\\n\\n
\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'
Preparation of Space Experiments edited by international leading expert Dr. Vladimir Pletser, Director of Space Training Operations at Blue Abyss is the 5,000th Open Access book published by IntechOpen and our milestone publication!
\n\n"This book presents some of the current trends in space microgravity research. The eleven chapters introduce various facets of space research in physical sciences, human physiology and technology developed using the microgravity environment not only to improve our fundamental understanding in these domains but also to adapt this new knowledge for application on earth." says the editor. Listen what else Dr. Pletser has to say...
\n\n\n\nDr. Pletser’s experience includes 30 years of working with the European Space Agency as a Senior Physicist/Engineer and coordinating their parabolic flight campaigns, and he is the Guinness World Record holder for the most number of aircraft flown (12) in parabolas, personally logging more than 7,300 parabolas.
\n\nSeeing the 5,000th book published makes us at the same time proud, happy, humble, and grateful. This is a great opportunity to stop and celebrate what we have done so far, but is also an opportunity to engage even more, grow, and succeed. It wouldn't be possible to get here without the synergy of team members’ hard work and authors and editors who devote time and their expertise into Open Access book publishing with us.
\n\nOver these years, we have gone from pioneering the scientific Open Access book publishing field to being the world’s largest Open Access book publisher. Nonetheless, our vision has remained the same: to meet the challenges of making relevant knowledge available to the worldwide community under the Open Access model.
\n\nWe are excited about the present, and we look forward to sharing many more successes in the future.
\n\nThank you all for being part of the journey. 5,000 times thank you!
\n\nNow with 5,000 titles available Open Access, which one will you read next?
\n\nRead, share and download for free: https://www.intechopen.com/books
\n\n\n\n
\n'}],latestNews:[{slug:"stanford-university-identifies-top-2-scientists-over-1-000-are-intechopen-authors-and-editors-20210122",title:"Stanford University Identifies Top 2% Scientists, Over 1,000 are IntechOpen Authors and Editors"},{slug:"intechopen-authors-included-in-the-highly-cited-researchers-list-for-2020-20210121",title:"IntechOpen Authors Included in the Highly Cited Researchers List for 2020"},{slug:"intechopen-maintains-position-as-the-world-s-largest-oa-book-publisher-20201218",title:"IntechOpen Maintains Position as the World’s Largest OA Book Publisher"},{slug:"all-intechopen-books-available-on-perlego-20201215",title:"All IntechOpen Books Available on Perlego"},{slug:"oiv-awards-recognizes-intechopen-s-editors-20201127",title:"OIV Awards Recognizes IntechOpen's Editors"},{slug:"intechopen-joins-crossref-s-initiative-for-open-abstracts-i4oa-to-boost-the-discovery-of-research-20201005",title:"IntechOpen joins Crossref's Initiative for Open Abstracts (I4OA) to Boost the Discovery of Research"},{slug:"intechopen-hits-milestone-5-000-open-access-books-published-20200908",title:"IntechOpen hits milestone: 5,000 Open Access books published!"},{slug:"intechopen-books-hosted-on-the-mathworks-book-program-20200819",title:"IntechOpen Books Hosted on the MathWorks Book Program"}]},book:{item:{type:"book",id:"6543",leadTitle:null,fullTitle:"State of the Art Virtual Reality and Augmented Reality Knowhow",title:"State of the Art Virtual Reality and Augmented Reality Knowhow",subtitle:null,reviewType:"peer-reviewed",abstract:"State-of-the-Art Virtual Reality and Augmented Reality Knowhow is a compilation of recent advancements in digital technologies embracing a wide arena of disciplines. 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\r\n\tOur rapidly shrinking, interconnected world is experiencing an unprecedented change in the face of digital innovation and emerging globalization. As the world’s population spirals beyond 7.7 billion, international economies are becoming more integrated and mutually dependent upon one other. These interconnected economies are subject to political, social, and cultural expectations unimagined in past decades. Employee skill sets that were in high demand only a few decades ago are now considered obsolete and unnecessary. New occupations are evolving in the face of digital advancement only to be quickly replaced by other emerging occupations more suitable to satisfying transitioning expectations. The changes are endless. Educational systems can no longer educate for today’s jobs. They must educate for tomorrow’s jobs. They must empower the future of their national economies while remaining mindful of the needs of tomorrow’s global economy. They stand at the intersection of globalization and technology. The only thing certain is change.
\r\n\r\n\tThis book is intended to examine the educational issues encountered in such an environment. The book aims to afford a fresh examination of theory, research, and practice into this field of study and to provide the reader with an insight into the challenges, successes, and opportunities encountered by today’s educational institutions.
",isbn:"978-1-83962-470-4",printIsbn:"978-1-83962-469-8",pdfIsbn:"978-1-83962-471-1",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"0cf6891060eb438d975d250e8b127ed6",bookSignature:"Dr. Sharon Waller, Dr. Lee Waller, Dr. Vongai Mpofu and Dr. Mercy Kurebwa",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/9536.jpg",keywords:"Global Skill Sets, Career Development, International Networking, Adult Education, World Education Culture, Modernization, International Standards, Educator Preparation, Educational Technology, Educational Impact, Curriculum Development, Sociocultural Issues",numberOfDownloads:998,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:0,numberOfTotalCitations:0,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"June 10th 2020",dateEndSecondStepPublish:"July 1st 2020",dateEndThirdStepPublish:"August 30th 2020",dateEndFourthStepPublish:"November 18th 2020",dateEndFifthStepPublish:"January 17th 2021",remainingDaysToSecondStep:"8 months",secondStepPassed:!0,currentStepOfPublishingProcess:5,editedByType:null,kuFlag:!1,biosketch:"Dr.Sharon Waller spent 13 years at a Sherman Independent School District where she served as an educational diagnostician, curriculum coordinator, and teacher, her teaching and research focus on special education, strategic educational leadership, and effective assessment of student learning.",coeditorOneBiosketch:"Prof. Lee Waller completed a Ph.D. in Higher Education Administration from the University of North Texas, he spent 17 years in the American community college system and served for 9 years at Texas A&M University-Commerce before joining the AURAK family.",coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"263302",title:"Dr.",name:"Sharon",middleName:null,surname:"Waller",slug:"sharon-waller",fullName:"Sharon Waller",profilePictureURL:"https://mts.intechopen.com/storage/users/263302/images/system/263302.png",biography:"Dr. Sharon Waller joined AURAK in March of 2015 as the founding manger of the Office of Counseling, Testing, and Disability Services. She has served as an Institutional Effectiveness (IE) coordinator as well as the chair of the Student Success Committee. She earned all three degrees from universities in Denton, Texas. Her Bachelor in Business Administration was earned at Texas Woman’s University, the Master of Education degree from the University of North Texas and her Philosophical Doctorate in Special Education (Inclusive Education) from Texas Woman’s University. She began her professional career as a public school teacher before transitioning into the role of admission, review and dismissal (ARD) facilitator. She quickly earned a certification as an educational diagnostician serving Sherman Independent School district for 13 years before coming to the United Arab Emirates. Sharon holds the rank of Assistant Professor in Education.\nWhile at AURAK she has developed the Office of Counseling, Testing, and Disability Services and has worked successfully with the Office of Institutional Effectiveness in various roles, supporting the ongoing growth of the university. She has experience in various aspects of the institutional effectiveness with a strength in analysis of outcomes and using data to make decisions.",institutionString:"American University of Ras Al Khaimah",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:null}],coeditorOne:{id:"263301",title:"Dr.",name:"Lee",middleName:null,surname:"Waller",slug:"lee-waller",fullName:"Lee Waller",profilePictureURL:"https://mts.intechopen.com/storage/users/263301/images/system/263301.png",biography:"Prof. Lee Waller joined the American University of Ras Al Khaimah in August of 2014. He currently holds the rank of Professor in Education. He served as a public-school teacher, community college teacher/administrator, and a university faculty/administrator before coming to the United Arab Emirates. He currently serves as Associate Provost of Enrollment Management. His baccalaureate and graduate degrees were earned at Stephen F. Austin State University. His PhD was earned at the University of North Texas. Lee is an experienced digital educator with substantial international didactic and administrative experience.",institutionString:"American University of Ras Al Khaimah",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:null},coeditorTwo:{id:"299343",title:"Dr.",name:"Vongai",middleName:null,surname:"Mpofu",slug:"vongai-mpofu",fullName:"Vongai Mpofu",profilePictureURL:"https://mts.intechopen.com/storage/users/299343/images/system/299343.jpg",biography:"Dr. Vongai Mpofu is a seasoned Science teacher educator with a strong background in school leadership and science teaching. She holds a Ph. D. in Science Education from the University of Witswatersrand in South Africa and have twelve years of University teaching experience at Bindura University of Science Education (BUSE). She joined University service at BUSE with a wealth of experience of heading several high schools in Zimbabwe. She has been in university leadership as a chairperson of the Department of Science and Mathematics Education as well as the acting Dean of the Faculty of Science Education. Dr. Vongai has a good record for teaching, research, and community engagement as well as qualities of good leadership. She is also engaged in journal editorship and peer reviews. She is actively involved in research and leadership related events inclusive of presenting conference papers and facilitating in research and leadership events. 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Currently, she is working in the Zimbabwe Open University’s Faculty of Education and Department of Educational Studies teaching courses in Educational management at both Bachelors and Masters levels. Mercy Kurebwa holds a Certificate in Education (Morgenster Teachers College), Bachelor’s Degree in Educational Administration, Planning and Policy Studies and a Master’s Degree in Administration, Planning and Policy Studies (University of Zimbabwe) and a Doctor of Philosophy Degree in Education (Zimbabwe Open University). Mercy Kurebwa has published 53 journal articles and has also presented over 20 papers at local and international conferences. The focus of the publications and presentations was on Assessment, Open and Distance Learning (ODel), Early Childhood Education, issues in schools, leadership and a few social issues. 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From chapter submission and review, to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. 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Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"878",title:"Phytochemicals",subtitle:"A Global Perspective of Their Role in Nutrition and Health",isOpenForSubmission:!1,hash:"ec77671f63975ef2d16192897deb6835",slug:"phytochemicals-a-global-perspective-of-their-role-in-nutrition-and-health",bookSignature:"Venketeshwer Rao",coverURL:"https://cdn.intechopen.com/books/images_new/878.jpg",editedByType:"Edited by",editors:[{id:"82663",title:"Dr.",name:"Venketeshwer",surname:"Rao",slug:"venketeshwer-rao",fullName:"Venketeshwer Rao"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"4816",title:"Face Recognition",subtitle:null,isOpenForSubmission:!1,hash:"146063b5359146b7718ea86bad47c8eb",slug:"face_recognition",bookSignature:"Kresimir Delac and Mislav Grgic",coverURL:"https://cdn.intechopen.com/books/images_new/4816.jpg",editedByType:"Edited by",editors:[{id:"528",title:"Dr.",name:"Kresimir",surname:"Delac",slug:"kresimir-delac",fullName:"Kresimir Delac"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"73116",title:"Bovine Mastitis: Part I",doi:"10.5772/intechopen.93483",slug:"bovine-mastitis-part-i",body:'\nBovine mastitis is one of the most important bacterial diseases of dairy cattle throughout the world. Mastitis is responsible for major economic losses to the dairy producer and milk processing industry resulting from reduced milk production, alterations in milk composition, discarded milk, increased replacement costs, extra labor, treatment costs, and veterinary services [1]. Annual economic losses due to bovine mastitis are estimated to be $2 billion in the United States [2], $400 million in Canada (Canadian Bovine Mastitis and Milk Quality Research Network-CBMQRN), and $130 million in Australia [3]. Many factors including host, pathogen, and environmental factors influence the development of mastitis; however, inflammation of the mammary gland is usually a consequence of adhesion, invasion, and colonization of the mammary gland by one or more contagious (Staphylococcus aureus, Streptocococcus agalactiae, Corynebacterium bovis, Mycoplasmsa bovis, etc.) or environmental (coliform bacteria, environmental Streptococcus spp. and some coagulase negative Staphylococcus spp., many other minor pathogens) mastitis pathogens.
\nOver 135 various microorganisms have been identified from bovine mastitis. The most common bovine mastitis pathogens are classified as contagious and environmental mastitis pathogens [4]. This classification depends upon their distribution in their natural habitat and mode of transmission from their natural habitat to the mammary glands of dairy cows [5]. It is important to mention that all pathogens lists as environmental or contagious may not be strictly environmental or strictly contagious; some of them may transmit both ways. Environmental mastitis pathogens exist in the cow’s environment, and they can cause infection at any time. Environmental mastitis pathogens are difficult to control because they are in the environment of dairy cows and can transmit to the mammary glands at any time, whereas contagious mastitis pathogens exist in the infected udder or on the teat skin and transmit from infected to non-infected udder during milking by milker’s hand or milking machine liners. Environmental mastitis pathogens include a wide range of organisms, including coliform bacteria (Escherichia coli, Klebsiella spp., Enterobacter spp., and Citrobacter spp), environmental Streptococcus spp. (Streptococcus uberis, Streptococcus dysgalactiae, Streptococcus equi, Streptococcus zooepidemicus, Streptococcus equinus, Streptococcus canis, Streptococcus parauberis, and others), Trueperella pyogenes, which was previously called Arcanobacterium pyogenes or Corynebacterium pyogenes and environmental coagulase-negative Staphylococcus species (CNS) (S. chromogenes, S. simulans, S. epidermidis, S. xylosus, S. haemolyticus, S. warneri, S. sciuri, S. lugdunensis, S. caprae, S. saccharolyticus, and others) [4, 6, 7, 8, 9] and others such as Pseudomonas, Proteus, Serratia, Aerococcus, Listeria, Yeast and Prototheca that are increasingly found as mastitis-causing pathogens on some farms [10, 11].
\nContagious mastitis pathogens primarily exist in the infected mammary glands or on the cow’s teat skin and transmit from infected to non-infected mammary glands during milking by milker’s hand or milking machine liners. Mycoplasma spp. may spread from cow to cow through aerosol transmission and invade the udder subsequent to bacteremia. The most frequent contagious mastitis pathogens are coagulase-positive Staphylococcus aureus, Streptococcus agalactiae, Mycoplasma bovis, and Corynebacterium bovis [11, 12]. The prevalence of mastitis caused by these different mastitis pathogens varies depending on herd management practices, geographical location, and other environmental conditions [13]. These different causative agents of mastitis have a multitude of virulence factors that make treatment and prevention of mastitis difficult.
\nIt is important to mention that all environmental mastitis pathogens may not be strictly environmental, and some of them may transmit both ways (contagious and environmental). However, the vast majority of these organisms are in the environment of dairy cows, and they transmit from these environmental sources to the udder of a cow at any time of the lactation cycle.
\n\nStreptococcus uberis is one of the environmental mastitis pathogens that accounts for a significant proportion of subclinical and clinical mastitis in lactating and non-lactating cows and heifers [14]. This organism is commonly found in the bedding material, which facilitates infection of mammary glands at any time [15]. Some report also indicated the possibility of contagious transmission of Streptococcus uberis [16].
\n\nS. uberis has various mechanisms of virulence that increases the chances of this organism establishing infection. These include a capsule, which evades phagocytosis, adherence to, and invasion into mammary epithelial cells [17, 18]. S. uberis adheres to epithelial cells using different mechanisms, including the formation of pedestals [19] and bridge formation through Streptococcus uberis adhesion molecule (SUAM) and lactoferrin [20, 21, 22]. This attachment is specific and mediated through a bridge formation between Streptococcus uberis adhesion molecule (SUAM) [23, 24] on S. uberis surface and lactoferrin, which is in the mammary secretion and has a receptor on the mammary epithelial surface [20, 22]. This interaction creates a molecular bridge that enhances S. uberis adherence to and internalization into mammary epithelial cells most likely via caveolae-dependent endocytosis and potentially allows S. uberis to evade host defense mechanisms [22, 24]. These factors increase the pathogenicity of S. uberis to cause mastitis. The sua gene is conserved among strains of S. uberis isolated from geographically diverse areas [9, 13], and a sua deletion mutant of S. uberis is defective in adherence to and internalization into mammary epithelial cells [14].
\nMore recently, coagulase-negative Staphylococcus species (CNS) such as S. chromogenes, S. simulans, S. xylosus, S. haemolyticus, S. hyicus, and S. epidermidis are increasingly isolated from bovine milk [7, 25, 26, 27] with S. chromogenes being the most increasingly diagnosed species as a cause of subclinical mastitis. Staphylococcus chromogenes [28] and other CNS [4, 8] have been shown to cause subclinical infections in dairy cows that reduce the prevalence of contagious mastitis pathogens.
\n\nStaphylococcus chromogenes is most commonly isolated from mammary secretions rather than from the environment itself [8, 29]. S. chromogenes consistently isolated from the cow’s udder and teat skin [30], and some studies showed that it causes long-lasting, persistent subclinical infections [26]. The CNS causes high somatic cell counts in milk on some dairy farms [29, 31]. Woodward et al. [32] evaluated the normal teat skin flora and found that 25% of the isolates exhibited the ability to prevent the growth of some mastitis pathogens. An in vitro study conducted on S. chromogenes showed that this organism could inhibit the growth of major mastitis-causing pathogens such as Staph. aureus, Strep. dysgalactiae, and Strep. uberis [28]. In a study conducted on conventional and organic Canadian dairy farms, CNS were found in 20% of the clinical samples [33]. Recently, mastitis caused by CNS increasingly became more problematic in dairy herds [30, 34, 35, 36]. However, mastitis caused by CNS is less severe compared to mastitis caused by Staphylococcus aureus [26].
\nColiform bacteria such as Escherichia, Klebsiella, and Enterobacter are a common cause of mastitis in dairy cows [37]. The most common species, isolated in more than 80% of cases of coliform mastitis, is Escherichia coli [38, 39]. E. coli usually infects the mammary glands during the dry period and progresses to inflammation and clinical mastitis during the early lactation with local and sometimes severe systemic clinical manifestations. Some reports indicated that the severity of E. coli mastitis is mainly determined by cow factors rather than by virulence factors of E. coli [40]. However, recent molecular and genetic studies showed that the pathogenicity of E. coli is entirely dependent on the FecA protein that enables E. coli to actively uptake iron from ferric-citrate in the mammary gland [41]. The severity of the clinical mastitis and peak E. coli counts in mammary secretions are positively correlated. Intramammary infection with E. coli induced expression and release of pro-inflammatory cytokines [42, 43]. Recently, it has been shown with mouse mastitis models that IL-17A and Th17 cells are instrumental in the defense against E. coli intramammary infection [44, 45]. However, the role of IL-17 in bovine E. coli mastitis is not well defined. The result of recent vaccine efficacy study against E. coli mastitis suggested that cell-mediated immune response has more protective effect than humoral response [46]. However, the cytokine signaling pathways that lead to efficient bacterial clearance are not clearly defined.
\nCoagulase-positive Staphylococcus aureus is one of the most common contagious mastitis pathogens in dairy cows, with an estimated incidence rate of 43–74% [47, 48]. Staphylococcus aureus is grouped under the family Staphylococcaceae and genus Staphylococcus. It is a gram-positive, catalase and coagulase-positive, non-spore forming, oxidase negative, non-motile, cluster-forming, and facultative anaerobe [49]. The coagulase test is not an absolute test for the confirmation of the diagnosis of S. aureus from the cases of bovine mastitis, but more than 95% of all coagulase-positive staphylococci from bovine mastitis belong to S. aureus [50]. Other coagulase-positive species include S. aureus subsp. anaerobius causes lesion in sheep; S. pseudintermedius causes pyoderma, pustular dermatitis, pyometra, otitis externa, and other infections in dogs and cats; S. schleiferi subsp. coagulans causes otitis externa (inflammation of the external ear canal) in dogs; S. hyicus is coagulase variable (some strains are positive and some others are negative), species that causes mastitis in dairy cows, exudative epidermitis (greasy pig disease) in pigs; and S. delphini causes purulent cutaneous lesions in dolphins.
\n\nS. aureus can infect many host species, including humans. In humans, S. aureus causes a wide variety of illnesses ranging from mild skin infection to a life-threatening systemic infection. It has been reported that certain strains of S. aureus with specific tissue tropism can be adapted to infect specific tissue such as the mammary gland [51]. Furthermore, a study by McMillan [52] showed distinct lineages of S. aureus in bovine, ovine, and caprine species. S. aureus strains can be host specific, meaning that they are found more commonly in a specific species [51]. Some studies showed that S. aureus that causes mastitis belong to certain dominant clones, which are frequently responsible for clinical and subclinical mastitis in a herd at certain geographic areas, indicating that the control measures may need to be directed against specific clones in a given area [53, 54, 55]. However, because S. aureus is such a big problem in human health, cross-infection has been an important research topic. Several studies have reported cases of cross-infection in several different species [56, 57, 58]. In the dairy industry, there have been reports of human origin methicillin-resistant S. aureus infecting bovine mammary glands [59, 60]. These studies add to the unease that strains can gain new mutations or virulence factors and adapt to cross the interspecies boundary relatively rapidly [61].
\nAlthough the incidence of S. aureus mastitis can be reduced with hygienic milking practices and a good management system, it is still a major problem for dairy farms, with a prevalence of 66% among farms tested in the United States [62]. The prevalence of S. aureus mastitis varies from farm to farm because of variation in hygienic milking practices and overall farm management differences on the application of control measures for contagious mastitis pathogens. Good hygiene in the milking parlor can significantly reduce the occurrence of new S. aureus mastitis in the herd, but it does not remove existing cases within a herd [63]. Neave et al. concluded that it is nearly impractical to keep all udder quarters of dairy cows free of all pathogens at all times. Since this early observation by Neave et al. [63], many studies have confirmed that management practices can reduce new cases of intramammary infection (IMI) [9, 64] but cannot eliminate existing infections. In the United States, the prevalence of clinical and subclinical S. aureus mastitis ranged from 10 to 45% [65] and 15 to 75%, respectively.
\n\nStaphylococcus aureus has many virulence factors that can be grouped broadly into two major classes. These include (1) secretory factors which are surface localized structural components that serve as virulence factors and (2) secretory virulence factors which are produced by bacteria cells and secreted out of cells and act on different targets in the host body. Both non-secretory and secretory virulence factors together help this pathogen to evade the host’s defenses and colonize mammary glands.
\nSome of surface localized structural components that serve as virulence factors include membrane-bound proteins, which include collagen-binding protein, fibrinogen-binding protein, elastin-binding protein, penicillin-binding protein, and lipoteichoic acid. Similarly, cell wall-bound factors such as peptidoglycan, lipoteichoic acid, teichoic acid, protein A, β-Lactamase, and proteases serve as non-secretory virulence factors. Other cell surface-associated virulence factors include exopolysaccharides, which comprises capsule, slime, and biofilm. Overall, S. aureus has over 24 surface proteins and 13 secreted proteins that are involved in immune evasion [66] and about 15–26 proteins for biofilm formation [67, 68].
\nSurface proteins, such as staphylococcal protein A (SpA), clumping factors A and B (ClfA and ClfB) [69, 70, 71], fibrinogen-binding proteins [72], iron-regulated surface determinants (IsdA, IsdB, and IsdH) [69, 73], fibronectin-binding proteins A and B [74], biofilm associated protein (BAP) and exopolysaccharides (capsule, slime, and biofilms) [75, 76, 77, 78, 79], play roles in S. aureus adhesion to and invasion into host cells [80]. The BAP expression enhances biofilm production and the BAP gene is only found in S. aureus strain from bovine origin [81, 82, 83]. Evaluation of BAP gene of S. aureus from bovine and human isolates using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) showed that bovine and human isolates are not closely related [84]. Thus, some host-specific evolutionary factors may have been developed between both strain types.
\nBiofilms are considered an important virulence factor in the pathogenesis of bovine S. aureus mastitis [77, 78]. Slime, an extracellular polysaccharide layer, acts as a barrier against phagocytosis and antimicrobials. It also helps with adhesion to a surface [85]. If a biofilm forms in a mammary gland, it will protect those bacteria from antimicrobials and the host’s immune system [77, 78]. In addition, once the biofilm matures and the immune attack has subsided, the biofilm can break open and allow reinfection of the mammary gland [86]. There are many contributors to biofilm production, such as polysaccharide intercellular adhesin (PIA) also known as poly-N-acetyl-β (1-6)-glucosamine (PNAG), MSCRAMMS, teichoic acids, and extracellular DNA (eDNA) [75, 76] that are known to help these bacteria cells to hold onto a surface [87]. Various proteins encoded by intercellular adhesion loci such as icaA, icaB, icaC, and icaD are involved in PIA production which in turn result in biofilm formation [75, 76]. Vasudevan et al. [88] evaluated the correlation of slime production and presence of the intercellular adhesion (ica) genes with biofilm production. These authors [88] found that all tested isolates were positive for icaA and icaD genes, and most tested isolates produce slime, but not all slime positives produced biofilms in vitro. Similarly, a study in Poland found that all isolates were positive for icaA and icaD [80] genes. While adhesion is promoted with biofilm production, the bap gene prevents the invasion of host cells [83]. Despite the presence of the ica gene strongly support biofilm production, the presence of the ica gene is not mandatory for biofilm production since S. aureus lacking ica gene can still produce biofilm through other microbial surface components recognizing adhesive matrix molecules (MSCRAM) and secreted proteins [89, 90].
\nSome of the known secretory virulence factors are toxins which include staphylococcal enterotoxins, non-enteric exfoliative toxins, toxic shock syndrome toxin 1, leucocidin, and hemolysins (alpha, beta, delta, and gamma) [91, 92]. Similarly, enzymes such as coagulase, staphylokinase, DNAase, phosphatase, lipase, phospholipase, and hyaluronidase serve as virulence factors of S. aureus [93].
\n\nS. aureus isolates from bovine mastitis produce alpha (α), beta (β), gamma (γ), and delta (δ) hemolysins that cause hemolysis of red blood cells of the host [94] and all are antigenically distinct. α-hemolysin is a pore-forming toxin that binds to a disintegrin and metalloproteinase domain-containing protein-10 (ADAM10) receptor resulting in pore formation and cellular necrosis [95, 96]. It is also known to increase the inflammatory response and decrease macrophage function [97]. α-hemolysin damages the plasma membrane of the epithelial cell resulting in leakages of low-molecular-weight molecules from the cytosol and death of the cell [98]. It is produced by 20–50% of strains from bovine IMI [99]. A study reported that the α-hemolysin might be required for a cell to cell interaction during biofilm formation [100]. β-hemolysin hydrolyzes the sphingomyelin present in the plasma membrane resulting in increased permeability with progressive loss of cell surface charge [101]. It is produced by 75–100% of S. aureus strains from bovine IMI [99]. α-hemolysin expression requires specific growth conditions in vitro because its growth is inhibited by agar [102]. α-hemolysin producing strains cause complete hemolysis of sheep red blood cells, whereas β-hemolysin producing strains cause partial hemolysis within 24 h of incubation at 37°C [103]. Partial hemolysis caused by β-hemolysin becomes completely lysed after further storage at 4–15°C, which is also expressed as hot-cold lysis [104]. β-hemolysin producing strains are the most frequent isolates from animals [105]. δ-hemolysin causes complete hemolysis of red blood cells of wide range of species including human, rabbit, sheep, horse, rat, guinea pig, and some fish erythrocytes. δ-hemolysin migrates more slowly through agar than the α-hemolysin so the effect takes longer time to express. Double (α- and β-) hemolysin producing strains caused complete hemolysis in the middle with partial hemolysis on the peripheral area around each colony [105]. γ-hemolysin is produced by almost every strain of S. aureus, but γ-hemolysin is not identifiable on blood agar plates, due to the inhibitory effect of agar on toxin activity [106].
\nThese toxins are heat stable and can resist pasteurization. S. aureus produces staphylococcal enterotoxins A, B, C, D, E, G, H, I, and J–Q as well as toxic shock syndrome toxin 1 (tsst-1) [105, 107, 108]. Enterotoxins can get into the food chain through the consumption of contaminated food and cause food poisoning [109]. Staphylococcal enterotoxins tend to contaminate dairy products and cause foodborne illness [110, 111]. Staphylococcal enterotoxins G to Q (SEG–SEQ) are prevalent among S. aureus isolates from cases of bovine mastitis and are also implicated in the pathogenesis of mastitis. Some of these toxins are known to function as superantigens that cause increased immunological reactivity in the host [110]. Some studies showed that about 20% of S. aureus isolates from IMI produce toxic shock syndrome toxin-1 [109, 112]. Toxic shock syndrome toxin causes toxic shock syndrome and can be fatal [113]. Besides the superantigenic effect of enterotoxins, their role in the pathogenesis of mastitis is unknown. It may be specific to each strain or area based on selective pressures in the habitat [114]. Enterotoxin prevalence seems to vary between geographical regions. The strains producing enterotoxin C have been isolated relatively frequently from cases of bovine mastitis [108, 115, 116].
\nEnterotoxins are believed to have a role in the development of mastitis since S. aureus isolates from cases of mastitis had a high prevalence of enterotoxins than isolates from milk of cows without mastitis [117, 118]; however, staphylococcal enterotoxins expressions are controlled by several regulatory elements [119] that respond to a variety of different micro-environmental stimuli and the exact mechanisms by which enterotoxins contribute to the development of mastitis are not clearly known and yet to be determined.
\nIn addition to specific virulence factors, Staphylococcus aureus also possesses different mechanisms or traits such as biofilm formation, adhesion to and invasion into mammary epithelial cells, and formation of small colony variant (SCV) that enable this pathogen to resist host defense mechanisms. The ability of S. aureus to invade mammary epithelial cells during mastitis plays a significant role in the pathogenesis of S. aureus. Internalized bacteria can hide from the host’s immune system inside the host cell and continue to multiply inside the host cell [120]. There may be many mechanisms that S. aureus uses to invade into host cells, and each mechanism can be strain dependent. S. aureus strains have a fibronectin-binding protein that can link to the fibronectin on the mammary epithelial cell surface. Fibronectin binding protein is thought to be a common way for the bacteria cells to invade bovine mammary epithelial cells. Fibronectin-binding protein-deficient strains cannot invade host cells [121]. The presence of a capsule prevents adherence to epithelial cells [122, 123].
\nAdhesion is the first step in the formation of biofilm or the invasion of host cells, which protects the bacteria from the host immune system and facilitates chronic infection [124]. Adhesion is dependent on surface proteins called adhesins, which help the bacterium to recognize and attach to host cells. Staphylococci are coated with a wide variety of surface proteins that help them to adhere to host cells and extracellular matrix components. Microbial surface components recognizing adhesive matrix molecules (MSCRAMMs) of the host are the most common surface proteins that are involved in adhesion [124]. The ability to bind to host tissue or the host’s cell surface is a pivotal part of the bacteria’s pathogenicity because adhesion is typically the first step in the invasion and biofilm formation [125, 126].
\nAdhesion to and invasion into epithelial cells [124], intracellular survival in macrophages [127], and epithelial cells allow them to avoid detection by the host immune system and resist treatment with antibiotics [120]. Due to its poor response to treatments, S. aureus infections often become chronic with a low cure rate [128]. Treatment of Staphylococcus aureus mastitis with cloxacillin cured only 25% of the clinical cases and 40% of subclinical cases in the study by Tyler and Baggot [129]. Staphylococcus aureus also has a known ability to form biofilms [77, 78, 86] and acquire antimicrobial-resistance genes via horizontal resistance gene transfer, which enables this bacterium to develop antimicrobial resistance [130, 131].
\nThe mode of transmission from infected mammary glands or colonized udder skin to healthy mammary glands is through contact during milking procedures with milker’s hand, towel, and milking machine [58]. S. aureus usually causes subclinical or chronic infections and is difficult to clear with antibiotic treatment [132].
\nThe most important virulence factor of S. agalactiae is the capsular polysaccharide [133], which protects this bacterium from being engulfed by macrophages and subsequently phagocytosed [133]. Another virulence factor of S. agalactiae is the Rib protein, which confers resistance to proteases. Emaneini et al. [133] found that the Rib encoding gene (rib) was detected in 89% of the isolates from bovine origin. Streptococcus agalactiae causes persistent infections that are usually difficult to clear without antibiotic treatment [134]. Though Streptococcus agalactiae is highly contagious, it has good response to treatment with antibiotics, which makes it possible to eliminate from herds with current mastitis control measures [129]. Since the adoption of hygienic milking practices, the incidence of mastitis caused by S. agalactiae has dramatically decreased and is now rarely observed in dairy herds [135].
\nMastitis caused by Mycoplasma spp. is a growing concern in the United States. It is believed that this organism has been underreported due to the difficulty of isolation by culture method [136]. The incidence of Mycoplasma mastitis varies across the globe, with a 3.2% prevalence rate in the United States that may increase to 14.4% in larger herd size of greater than 500 cows [47, 48, 62, 137]. A risk factor for Mycoplasma mastitis increase with herd size, and most of the Mycoplasma mastitis cases are subclinical infections with outbreaks linked to asymptomatic carriers [138]. Pathogenesis of most Mycoplasma spp. infection is characterized by adherence to and internalization into host cells resulting in colonization of the host with immune modulation without causing severe disease [138]. Mycoplasma species lack a cell wall, thus not sensitive to beta-lactam antibiotics, but showed sensitivity to non-beta-lactam antibiotics [139].
\nIn general, it is believed that mastitis pathogens gain entrance to the udder through teat opening into the teat canal and from the teat canal into the intramammary area during the reverse flow of milk due to vacuum pressure fluctuation of the milking machine [9]. However, the detailed mechanism of mastitis pathogen colonization of the mammary gland may vary among species of bacteria and the virulence factors associated with particular strain in each species. An example of this is in some cases; it has been shown that E. coli can penetrate the teat canal without the reverse flow of milk [9]. Some of the major mastitis pathogens, such as E. coli [140], Staphylococcus aureus, and Streptococcus uberis [20, 21, 22] can adhere to and subsequently invade into the mammary epithelial cells. This adherence and subsequent invasion into mammary epithelial cells allow them to persist in the intracellular area as well as to escape the host immune defenses attack and action of antimicrobial drugs [120, 140, 141, 142, 143, 144]. Dogan et al. [145] compared E. coli strains known to cause chronic infections with strains known to cause acute infections and found that chronic strains were more invasive to the epithelial cells, leading to the difficulty in clearance and persistent infection compared to acute strains. S. aureus enters the mammary gland through the teat opening and subsequently multiply in the mammary gland where they may form biofilms, attach to, and internalize into the mammary epithelial cells causing inflammation of mammary glands characterized by swelling, degeneration of epithelial cells, and epithelial erosions and ulcers [146, 147].
\nDepending on clinical signs, mastitis can also be divided into clinical and subclinical mastitis. Clinical mastitis is characterized by visible inflammatory changes (abnormalities) in the mammary gland tissue such as redness, swelling, pain, increased heart, and abnormal changes in milk color (watery, bloody, and blood tinged) and consistency (clots or flakes) [9]. Clinical mastitis can be acute, peracute, subacute, or chronic. Acute mastitis is a very rapid inflammatory response characterized by systemic clinical signs which include fever, anorexia, shock, as well as local inflammatory changes in the mammary gland and milk. Peracute mastitis is manifested by a rapid onset of severe inflammation, pain, and systemic symptoms that resulted in a severely sick cow within a short period of time. Subacute mastitis is the most frequently seen form of clinical mastitis characterized by few local signs of mild inflammation in the udder and visible changes in milk such as small clots. Chronic mastitis is a long-term recurring, persistent case of mastitis that may show few symptoms of mastitis between repeated occasional flare-ups of the disease where signs are visible and can continue over periods of several months. Chronic mastitis often leads to irreversible damage to the udder from the repeated occurrences of the inflammation, and often these cows are culled.
\nSubclinical mastitis is the inflammation of the mammary gland that does not create visible changes in the milk or the udder. Subclinical mastitis is an infection of mammary gland characterized by non-visible inflammatory changes such as a high somatic cell count coupled with shedding of causative bacteria through milk [9]. During this inflammatory process, the milk samples showed a rapid increase of somatic cells, characterized by increased number of neutrophils in the secretion [146, 148]. Despite increased recruitment of somatic cells into infected mammary glands, evidenced by an increased number of neutrophils, infection usually does not clear but became subclinical. Intramammary infections during early lactation may become acute clinical mastitis characterized by gangrene development due congestion and thrombosis (blockage) of blood supply to the tissue but most new infection during late lactation or dry period become acute or chronic mastitis [149, 150].
\nThe increase in somatic cell count during subclinical infections leads to a decrease in useful components in the milk, such as lactose and casein [151]. Lactose is the sugar found in milk, and casein is one of the major proteins in milk and decreases in these two components affect the quality and quantity of milk yield [9]. During mastitis, there is an increase in lipase and plasmin, which have a detrimental effect on the quantity and quality of milk due to the breakdown of milk fat and casein [9]. Subclinical infections can reduce milk production by 10–12% when just one-quarter is infected [152]. These subclinical infections cause some of the greatest unseen economic [20] losses because of their detrimental impact on production and milk quality without showing visible signs of infection [152].
\nThere are host-, pathogen-, and environmental-related risk factors that predispose dairy cows to mastitis. The host risk factors include age (parity), stage of lactation, somatic cell count, breed, the anatomy of the mammary glands/morphology of udder and teat (diameter of teat canal and conformation of the udder), and immune competence (immunity) [153] (Figure 1). The environmental risk factors include the proper functioning status of milking machine, udder trauma, sanitation, climate, nutrition, management, season, and housing condition [154] (Figure 1). The pathogen risk factors include type (bacteria, fungi, yeast, and algae), number (large number and small number), virulence (highly, moderate, or less virulent), frequency of exposure (dirty farm floor, dirty milking machine, and dirty teat drying towels frequently expose to pathogen; clean floor, clean milking machine, and clean teat drying towels less exposure to pathogens), ability to resist flushing out of the glands by milk (ability to adhere or attach to and invade or internalize into mammary epithelial cells), zoonotic (transmit from cow to human or vice versa) potential, and resistance to antimicrobials [4] (Figure 1). The warm, humid, and moist climate favors the growth of bacteria and increases the chances of intramammary infection (IMI) and mastitis development [154]. The incidence of mastitis varies from farm to farm due to the combined effects of these different factors that increase the risk of disease development.
\nRisk factors for mastitis. SA, Staphylococcus aureus; EC, Escherichia coli; SU, Streptococcus uberis; SCC, somatic cell count; AMR, antimicrobial resistance.
Dairy cows are highly susceptible to IMI during the early dry period due to increased colonization of teat skin with bacteria. Bacterial colonization of teat increases during the early dry period because of an absence of hygienic milking practices including pre-milking washing and drying of teats [155], as well as pre- and post-milking teat dipping in antiseptic solutions [156, 157] that are known to reduce teat end colonization and infection. An udder infected during the early dry period usually manifests clinical mastitis during the transition period because of increased production of parturition inducing immunosuppressive hormones [158, 159], negative energy balance [160], and physical stress during calving [161].
\nMastitis is increasingly becoming a public health concern due to the ability of the causative bacterial pathogens and/or their products, such as enterotoxins, to enter the food supply and cause foodborne diseases [109, 162], especially through the consumption of raw milk [29] and undercooked meat of culled dairy cows due to chronic mastitis that are usually sold to the slaughter (abattoir) for meat consumption. The Center for Disease Control (CDC) estimated that roughly 48 million people in the United States a year become sick from foodborne diseases [163]. Foodborne pathogens have been detected in bulk tank milk in multiple studies [164, 165, 166, 167]. These authors found that the number of foodborne pathogens detected in bulk tank milk vary with location, management practices, hygiene, and number of animals on the farm [165]. Similarly, a study on bulk tank milk from east Tennessee and southwest Virginia by Rohrbach et al. [168] showed that 32.5% of the samples analyzed contained one or more foodborne pathogens. Even dairy producers who used proper hygienic milking practices, pre- and post-milking teat disinfectant and antibiotic dry cow therapy, had foodborne pathogens in their bulk tank milk [164]. The isolation of these foodborne pathogens from bulk tank milk samples across the United States demonstrate the threat that mastitis pathogens and zoonotic mastitis causing pathogens create on public health if raw milk is consumed or if these pathogens make it through processing.
\nBovine mastitis is the most important multifactorial disease of dairy cattle throughout the world. Mastitis is responsible for huge economic losses to the dairy producers and milk processing industry due to reduced milk production, alterations in milk composition, discarded milk, increased replacement costs, extra labor, treatment costs, and veterinary services. Many factors including pathogen, host, and environment can influence the development of mastitis. Mastitis, the inflammation of the mammary gland is usually a consequence of adhesion, invasion, and colonization of the mammary gland by one or more mastitis pathogens such as Staphylococcus aureus, Streptococcus uberis, and Escherichia coli.
\nSpinal cord injury (SCI) is an event that affects the quality of life of patients as a consequence of affected sexual function, impaired sensory and motor function, including bowel and bladder control, walking, eating, grasping, pain, and spasticity [1, 2, 3]. For many years, SCI has been considered irreversible [4]. However, research on plasticity after SCI has opened new paths and generated a shift in rehabilitation of SCI patients in the past three decades: its former focus on learning compensatory movements to regain function gradually changed to restoration of function through repetitive movement training combined with the stimulation of the nervous system [5].
\nThe term neural plasticity describes the ability of the nervous system to adapt a new functional or structural state in response to intrinsic or extrinsic factors [6]. Thus, plasticity encompasses the underlying mechanisms that lead to a spontaneous return or recover of motor, sensory and autonomic functions to different degrees. The concept of plasticity at the cellular level can be tracked back to Ramon y Cajal’s work, who suggested that modification of synaptic connections could play a very important role in memory [7]. After that, the work of Donald Hebb was very important to the concept of long-term potentiation (LTP), namely by suggesting that two neurons that fire together and are close enough may grow some connections or undergo metabolic changes that increase their ability to communicate [8]. This happens because chemical synapses have the ability to change their strength [9].
\nSensory information from Ia afferent fibers (transmitting information about muscle activity and movement) play an essential role in inducing functional and morphological changes that lead to the maturation of the brain and the spinal cord [9], independently of the SCI level and whether it is complete or incomplete [10]. Thus, activity-dependent plasticity refers to the changes in the central nervous system (CNS) associated with movement [9] and reflects one of the basic forms of learning in humans [11]. These neural changes happen throughout the life span at both the brain and spinal cord level. However, not all plasticity is beneficial: adverse changes may also appear [12]. This is known as maladaptive plasticity and encompasses events such as excessive plasticity associated with some disease symptoms like focal dystonia, spasticity, and chronic pain. Current SCI rehabilitation is based on task-specific programs aiming at promoting neurorecovery through beneficial activity-dependent plasticity and avoiding maladaptive plasticity [6].
\nThis chapter summarizes the main effects on motor and functional recovery, as well as spasticity and pain, when using noninvasive modalities in the rehabilitation of SCI patients, either in the research or the clinical setting. Some of these techniques aim at stimulating different levels of the central (brain or spinal cord) and peripheral nervous system, while others combine some sort of stimulation with devices that may assist and allow for repetitive motor training (e.g., hybrid exoskeletons and FES driven cycling).
\nRecent research has shown that even complete SCI patients may preserve some residual pathways connecting supraspinal and spinal circuits [13]. Given that these patients may preserve muscle activity below the level of injury, target rehabilitation for SCI also includes modalities that stimulate the brain. This might strengthen the efficacy of the residual neural pathways and, therefore, improve volitional control after SCI [14]. This section describes two different types of noninvasive brain stimulation (NIBS): repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS). Both techniques have been used in the research and clinical setting aiming at improving motor and functional recovery, as well as spasticity and pain after SCI [4].
\nTranscranial magnetic stimulation (TMS) is a form of noninvasive brain stimulation in which short magnetic fields are generated by a coil in order to induce electric current pulses in the brain, which can then elicit depolarization and action potentials in cortical neurons (see Figure 1). Since its first application in humans in 1985, TMS has become a standard electrophysiological technique to assess the excitability of the corticospinal circuitry, due to its usability and ability to directly activate brain structures without causing harm to the subject. The most extended protocol applies single TMS pulses to activate motor cortex at a specific area where topographic projections of a group of muscles are represented. This cortical activation elicits action potentials that propagate until reaching the muscles, inducing a motor evoked potential (MEP), which can be measured by electromyography (EMG) [2].
\nThe magnetic field generated by the TMS coil will induce electric current pulses in the brain, which can elicit depolarization and action potentials in cortical neurons.
Repetitive transcranial magnetic stimulation (rTMS) is a form of TMS where several TMS pulses are applied sequentially in order to induce long-term changes in the targeted neural pathways. The underlying physiological mechanism of rTMS lies in the repeated activation of a network of synapses that may lead to long-term potentiation (LTP) or long-term depression (LTD) of those synapses [4]. The induction of long-term changes in neural circuits using rTMS can be applied to revert the effects of neurological disorders. For instance, rTMS received FDA approval and has become a promising treatment for major depression.
\nDue to its ability to induce long-term changes in neural systems, rTMS has been also applied in patients with motor disorders as a modality to modulate the activity of residual (cortical, subcortical, and corticospinal) pathways and thus promote functional recovery [2]. Moreover, rTMS has been applied in a wide range of protocols, with varying frequencies and intensities of stimulation, or even the number of pulses and sessions, among others. The main stimulation protocols explored so far may be encompassed in the following:
Theta burst stimulation (TBS) consists of three 50 Hz pulses delivered in blocks at 200-ms interval (5 Hz). Intermittent TBS (iTBS) involves the delivery of TBS for 2 s, followed by a resting period of 8 seconds, for a total of 3 min; this is hypothesized to facilitate LTP [15]. On the other hand, continuous TBS (cTBS) applied in 40 s blocks promote LTD.
QuadroPulse (qQPS) applies four high-frequency pulses repeated every 5 s. The facilitator or inhibitory excitability effects depend on the inter-pulse intervals.
I-wave protocol involves the repetitive stimulation of the motor cortex at 1.5 ms rate, seeking to mimic the indirect waves (I-waves) of corticospinal neurons and to increase their excitability [4].
Paired associative stimulation (PAS) relies on the Hebb’s theory, which states that a synaptic connection is enhanced when two stimuli converge in time repeatedly. PAS protocol combines a peripheral nerve stimulus with a TMS pulse over the motor cortex, aiming to pair both stimuli in time at the cortex, which will promote corticospinal excitability. PAS can present different variants, in which the TMS pulse can be replaced by physiological activation of the motor cortex (e.g., imaginary movement), or the pairing site targets of TMS and peripheral stimulus are the motoneurons at the spinal cord.
Regardless of its incipient stage and current limitations, rTMS has become a promising approach for SCI rehabilitation, not only to improve motor function but also to decrease spasticity and neuropathic pain. This technique enables targeting and promoting long-term changes in neural pathways, by exploiting the plastic properties that may facilitate function recovery. Improvements seem to be present when higher rTMS stimulus intensities are used [2]. On the other hand, the few studies that investigated the effects of rTMS on spasticity in iSCI patients reported some reduction in the clinical symptoms of spasticity [2]. Moreover, the few studies that tested the effect of rTMS on neuropathic pain reported some reductions in the clinical symptoms of pain [2].
\nNotwithstanding, these results hold a great variability, are not reproducible in all patients, and are limited to certain clinical assessment scales or neurophysiological measurements. Several constraints can explain current limitations of the rTMS application in SCI patients. First, there is a shortage of studies providing evidences of sustained benefits of rTMS therapy beyond conventional treatments. Besides the different stimulation protocols and parameters applied, type of lesion and nonuniform assessment methodologies hamper the development of consistent evidences. Although evidences so far do not suggest any harm to the subjects, safety issues should be also considered when using rTMS in SCI patients, especially because of the high threshold needed to evoke motor responses in the impaired pathways [16].
\nMore research is needed to provide robust evidence that can support the use of rTMS as an alternative to standard therapies. In addition to bigger sample sizes used in each study, researchers should also test the same (or very similar) stimulation parameters and protocols to provide reproducible results. Finally, it is critical to better understand the pathophysiology of neural structures affected by rTMS to design optimal and customized protocols that might boost beneficial neural changes coupled with functional recovery after SCI [2].
\nTranscranial direct current stimulation (tDCS) is a technology that delivers continuous low current stimulation (1–2 mA) via paired anode and cathode electrodes over the scalp [4, 14, 17] (see Figure 2). This modality is usually combined with motor training to promote activity-dependent plasticity [14]. tDCS may change brain function by causing neurons resting potential to depolarize or hyperpolarize. Depolarization happens when positive stimulation (anodal tDCS) is delivered, which increases neural excitability and, therefore, neural firing. Cathodal tDCS (negative stimulation) causes hyperpolarization and, thus, decreases neural firing [4].
\nTranscranial direct current stimulation delivers continuous low current stimulation by applying a positive (anodal) or negative (cathodal) current via paired electrodes over the scalp.
This technique is still in the early stage. To our knowledge, just seven studies have examined improvements in motor function after SCI related to the use of tDCS: four studies evaluated its effect on upper limb function [18, 19, 20, 21] and three studies evaluated the tDCS effect on lower limb function and gait [22, 23, 24]. All these studies used anodal stimulation and showed improvements in upper and lower limb motor function.
\nThe use of tDCS has led to improvements in pinch force, manual dexterity, and force modulation when combined with repetitive practice [18]. Other study reported that stimulation intensity affects functional outcomes when tDCS was delivered at rest: increased corticospinal excitability to affected muscles was obtained when using 2 mA stimulation, but not 1 mA, in nine chronic SCI patients [19]. Another study also reported gains in hand motor function after a single session of 2 mA tDCS, though no improvements were described in clinical scales [20]. When combining tDCS with robot-assisted arm training, SCI patients improved arm and hand function post-treatment and at the 2-month follow-up [21].
\nThe three studies that evaluated the tDCS effect on lower limb function and gait showed improved motor function [22, 23, 24]. However, one of these studies combined tDCS with robotic gait training and also showed no significant differences between these improvements and those verified in the group who received sham stimulation combined with robotic gait training [22].
\ntDCS is an attractive noninvasive modality option for the treatment after SCI: it is affordable and does not present substantial adverse events (when present, they included redness of the skin, sleepiness, headache, and neck pain [4]). However, further research is still needed to provide robust evidence that support the use of tDCS to improve motor function and to be used in the clinical setting as a long-term strategy after SCI.
\nIn the recent years, spinal cord electrical stimulation (SCS) has arisen as a promising tool to modulate corticospinal excitability and modify the motor output in SCI individuals. The most extended form of SCS is epidural SCS, which consists on delivering electrical currents through arrays of electrodes implanted in the epidural space of the spinal cord, in order to modify the excitatory output of the spinal cord. It has been widely studied as an application for chronic pain relief [14]. Promising results from a recent research showed its potential to improve neurological recovery and support the activities of daily living (including walking) after SCI [25].
\nTranscutaneous spinal cord stimulation (tcSCS) is a novel form of SCS that delivers superficial stimulation, usually over the skin that overlies the lower thoracic and/or lumbosacral vertebrae [26]. The principles underlying tcSCS rely on the physiology of the corticospinal pathways in the spinal cord that can produce excitability changes in the different neural populations of the spinal circuitry [27, 28]. Central pattern generators (CPGs) are pools of neurons able to elicit rhythmic and coordinated movements without the contribution of supraspinal centers. CPGs use proprioceptive information to provide real-time and coordinated control of motor output. The propriospinal system serves as an integratory interface between supraspinal and spinal centers, modulating motor activity. tcSCS is able to modulate the excitability properties of these systems by means of different stimulation protocols, in which the surface array placement along the spinal cord, direction of the current, intensity, frequency, and timing of stimulation result in different modulation outcomes. tcSCS was able to activate GPGs in healthy volunteers, eliciting coordinated and synchronized nonvoluntary movements of the lower limb [28]. These findings have been reproduced in SCI individuals, namely by reactivating damaged spinal circuitries that were previously considered as nonfunctional. When tcSCS was applied over several training sessions in SCI patients, there was improved voluntary modulation of movement of the lower limbs [29]. Moreover, combining tcSCS training with pharmacology therapy and exoskeletons increased motor control enhancement [26].
\ntcSCS overcomes the invasiveness and costs of epidural SCS with the trade-off of poor spatial stimulation resolution. Although the number of studies using this technique is considerably low, and the exact physiological mechanisms behind the improvements shown are still yet to be fully understood, tcSCS is already a promising tool to be considered in future SCI rehabilitation. Multi-approach therapies including tcSCS, pharmacological, active movement, and robotic-assisted training should be considered to exploit the combination of different physiological effects produced by each modality and maximize motor recovery [26].
\nMotor control and the execution of voluntary movements require the interaction between afferent feedback and supraspinal input to accurately plan and execute movements. This interplay induces activity-dependent plasticity at both the brain and spinal cord level [30, 31]. After SCI, afferent feedback is impaired and becomes essential to reorganize spinal circuits below the lesion area [30]. Therefore, noninvasive modalities that apply surface electrical stimulation at the peripheral level (either alone or combined with assisted training) to augment or modify neural function are very appealing and have been applied in SCI rehabilitation.
\nThis section overviews two forms of surface stimulation that are user friendly and can be easily administered by a therapist during SCI rehabilitation: transcutaneous electrical nerve stimulation (TENS) and functional electrical stimulation (FES). The second part of this section reports the main results attained when using cycling driven by electrical stimulation and the combination of electrical stimulation with external robotic devices.
\nTENS is the most common noninvasive modality used in physical therapy [32]. This type of stimulation delivers high-frequency (50–150 Hz) and low-intensity (below motor threshold) surface electrical current [33].
\nThough TENS has been commonly used in pain control and to reduce muscle stiffness/tone, there are also some reports on decreased spasticity due to the use of this modality. For instance, TENS has recently reduced spasticity in SCI patients and the effects outlasted up to several hours after treatment [34]. This is because TENS activates sensory nerves that in turn may activate inhibitory interneurons that will inhibit the spastic muscle activity [34]. More specifically, these anti-spastic effects are due to the release of gamma-aminobutyric acid (GABA) that acts as inhibitory neurotransmitters, achieving similar anti-spastic effects to those of baclofen [32], which is a first-line treatment for spasticity, especially in adults who suffered a SCI [35]. Results of spasticity treatment using TENS seem to improve when combined with physical therapy [36].
\nGiven its low cost, lack of adverse event effects, and ease to use, TENS seems to be a very good solution to treat spasticity after SCI. Moreover, since TENS alleviates pain and fatigue and can be used for periods of several hours, it seems to be appropriate for the beginning of the rehabilitation after SCI, when training is not very intensive.
\nFES is another modality of electrical stimulation that has become very popular in the clinical setting. FES is similar to TENS in the sense that the two modalities use electrodes on the skin to provide electrical stimulation to a desired location of the body; but they differ in the settings and especially in the purpose of their use. Unlike TENS, FES delivers trains of electrical stimulation above motor threshold to stimulate a muscle or the efferent nerve supplying a muscle in order to attain a muscle contraction [14]. The higher the amplitude of this stimulation, the bigger is the number of recruited efferent fibers and, therefore, the higher the muscle contraction.
\nFES has been used to restore bladder and bowel control, as well as sexual function, which are ranked among the most important functions to regain among SCI patients [37]. FES has also been widely used for the treatment of muscle weakness, gait training, and muscle reeducation [34]. In the case of SCI, it is well known that artificially induced contraction of weak or paralyzed muscles brings several therapeutic benefits, such as prevention of lower limb muscle atrophy, increased muscle strength, endurance, and cardiovascular fitness [38, 39]. In addition to these benefits, the coordinated stimulation of efferent nerves (usually to stimulate agonist-antagonist muscles of a joint) can be paired with a functional activity to produce a given biomechanical task and, thus, restore motor function [34].
\nOn the other hand, there is evidence that peripheral stimulation, if synchronized with patients’ voluntary effort, can further promote recovery [14]. In fact, improved modulation together with volitional control seems to be key factors to reinforce connectivity during rehabilitation of SCI patients, presumably through synaptic enhancement [14]. In this sense, brain-machine interfaces (BMIs) are currently the most sophisticated neuromodulation tools to restore voluntary limb movements after SCI. In the context of the noninvasive modalities described in this chapter, BMIs can be used to stimulate the peripheral nervous system by use of decoded brain signals recorded with electroencephalography (EEG) [14].
\nFinally, FES has also been used to reduce spasticity in SCI patients, usually by stimulating the spastic muscle. This is hypothesized to modulate recurrent inhibition via Renshaw cells [34]. These inhibitory interneurons are excited by collaterals of the axons of motoneurons and make inhibitory synaptic connections with several populations of motoneurons, including those that excite them [40]. This reciprocal inhibition is important to prevent overshooting muscle contraction induced by FES.
\nDespite all the benefits here described, FES presents several challenges for tasks that are executed for long periods of time. Limited muscle force generation, rapid onset of muscle fatigue, and nonlinear, time-dependent mechanical responses, as well as the redundancy of the musculoskeletal system are the main challenges of this technology that traditionally hamper generalized use for rehabilitation and/or motor compensation of walking. However, multi-electrode techniques are showing promising results [41] and should be explored.
\nPhysical activity of SCI people whose limbs are paralyzed is very important to maintain their physiological well-being. A promising approach is the application of FES during cycling movements. This technique, called FES cycling, is a noninvasive training protocol used in medical rehabilitation, mostly addressed to individual affected by SCI. This method can be applied continuously for tens of minutes, with direct benefits on muscle strength. Besides muscle strengthening, FES cycling is beneficial for cardiovascular and respiratory functions [42].
\nFES training for lower limb muscles can be performed on stationary cycle ergometers or mobile tricycles. As shown in Figure 3, FES is managed by a controller, which receives signals from a crank angle sensor and, depending on the actual crank position, transfers sequences of electrical impulses to surface electrodes to stimulate muscles and generate active muscle force. The power output produced by the application of FES depends on three main aspects. The first is the number of muscle groups stimulated. The second is the parameters of the stimulating current, that is, amplitude, pulse width, and frequency. The third is the timing of the stimulating signal sent to the individual muscles.
\nFES driven cycling: a controller sends electrical signals (stimulation current) to selected muscles. The actual muscle forces depend on the actual crank angle value transferred to the controller and on the parameters and timing of the stimulation signals sent to individual muscles.
FES cycling is usually applied on several lower limb muscles simultaneously [43]. The main muscle groups considered are the hamstrings and quadriceps and, in some cases, the gluteus maximus. The quadriceps are stimulated either as a whole, that is, using only one pair of electrodes, or more selectively, in which three muscles composing them—that is, the vastus medialis, vastus lateralis, and rectus femoris—are stimulated individually. This more selective stimulation has demonstrated, in a recent pilot study, to improve up to 27% the power output in one patient with spastic muscles [44]. In this case, while the total stimulation current (the sum of the amplitude of currents applied in all of the channels) was higher, lower stimulation current amplitudes per muscle groups were sufficient to generate the required movement. The average current amplitude applied in FES cycling in SCI individuals is around 50–70 mA per muscles and it varies in a wide range. In some protocols, the current amplitude is increased until 120–140 mA to achieve power output around 10 W [45] and in extreme cases 20 W [46]. Others stimulated muscles with a frequency of 30 Hz, current amplitude of 70–90 mA, and pulse width of 500 μs, reaching a power output around 30 W [47]. The timing of stimulation is usually set according to recorded and processed muscle activities of able-bodied persons and/or on physiological, biomechanical parameters of the muscles and limbs of the participants. Nevertheless, these approaches are either not adaptive to the patient-specific musculoskeletal conditions, or very difficult to calibrate. For instance, when applying selective stimulation of the three quadriceps muscles separately [44], we found that the participant, even reaching higher power output, preferred to cycle for a shorter time, possibly due to a nonphysiological stimulation strategy. In our opinion, more studies are needed to explore these control combinations, in particular considering the case of selective stimulation. This will likely lead to new more efficient, natural, and adaptable stimulation protocols.
\nCadence is another important variable in FES-cycling rehabilitation. In the case of ergometer-based training, cadence is on average set to 45–50 rpm, in most of the stimulating conditions. To adapt the treatment to patient residual motor ability, cadence can be changed in combination with various crank resistances during the rehabilitation process. Tricycles have been proposed as an alternative to stationary cycle ergometers [48]. A recent study reported that the series of FES trainings on a tricycle resulted in increased speed of cycling of paraplegics with denervated muscles [49], which is normally not observed in similar ergometer-based protocols. FES-driven tricycling is gaining relevance, as testified by several competitions organized during the last couple of years [50, 51, 52, 53]. However, these competitions are only targeting people with SCI. We expect that wider range of participants, for example, stroke, will also be addressed in the near future, as supported by recent promising research works in this direction [54, 55].
\nRepetitive and intensive task-specific training drives beneficial neuroplasticity, thus enhancing functional recovery [56]. Therefore, exoskeletons for motor rehabilitation purposes have emerged in the last decade as a convenient technology that allow multiple, intensive, and more effective sessions of gait training, allowing SCI patients to ameliorate their performance in daily life [56]. Moreover, a study reported that spasticity and pain intensity of SCI patients decreased after one single session of walking assisted by a powered robotic exoskeleton [56].
\nA paradigmatic development of a stationary rehabilitation robot for gait training is the Lokomat system, which combines body-weight supported treadmill-training (BWSTT) with the assistance of a robotic gait orthosis. These robotic systems are able to provide guidance forces to the lower limb segments to induce a consisting stepping pattern with adjustable guidance. It has been shown that although the mechanical coupling and added guidance may change the task constraints and in turn alter voluntary leg movements, the basic neuromuscular pattern is preserved when intact humans walk assisted by this robot [57]. Robot-assisted gait training with the Lokomat after SCI has been shown in some studies to improve outcomes related to mobility when compared to conventional overground training [58, 59]. For example, it was shown improved gait distance, strength, and functional level of mobility and independence of acute SCI patients receiving robotic-assisted gait training than the group of patients receiving conventional overground training [60]. Also, it has been demonstrated that robot-assisted gait training combined with conventional physiotherapy could yield more improvement in ambulatory function of SCI patients than conventional therapy alone. However, the impact of such complementary tools to provide neuromuscular education is still not well established for a convincing penetration of these systems in the clinical rehabilitation environments. Some limitations of such stationary robotic tools are that robotic-assisted training can be limited in the range of gait speed at which the exoskeleton robot can provide a comfortable gait pattern. Also, the stationary machine imposes restrictions to the user movements to the sagittal plane, significantly preventing motion in the frontal and transversal plane that are required for overground walking.
\nWearable robots (WR) for overground untethered assisted walking are emerging devices that have the potential to overcome some of the above-mentioned constraints and opening a range of clinical application scenarios. Through wearable mechanical actuation and sensing, WRs are proliferating for their use as assistive and rehabilitation technologies due to their ability to replicate the complex motions involved in human movement. As a result, the past few decades have seen an increasing amount of research focused on developing robotic systems intended to interact with the neurologically impaired human body. This interaction (of the human body) with WRs has been established in foundational literature [61] as dual, bidirectional physical (pHRi), and cognitive (cHRi) interactions. While these systems have been proven to be useful for specific applications, such as in-clinic rehabilitation, current research in the area of pHRi for WRs is focusing more on developing lightweight and flexible force interactions with hardware solutions that might be more suitable to a broader range of applications (by adding compliance to rigid exoskeletons [62, 63] or developing “soft exosuits” [64]). However, these soft exoskeletons are in early stage and the majority of clinical evidence of their efficacy for treatment of SCI is in studies with motorized powered exoskeletons. A systematic review of the literature on powered WRs for overground gait rehabilitation pointed out that, although current technology is still under development, and hence its ultimate impact remains still unclear, a number of revised studies report positive changes in outcome variables and suggest that training time and improvements in gait speed using powered WRs are correlated in SCI population [65].
\nOn the cHRi side, efforts are focused on developing means for interpretation of mechanical and neural signals to establish adequate control methods that integrate WRs as parts of human functioning. In this regard, a scheme for “symbiotic interaction” between humans and WRs has been recently developed in the FET Project BioMot (FP7-ICT-2013-10-611695), yielding new technologies to interface human neuromechanics with robot-control algorithms to guide assistance; the point of increasing their proficiency is to make them more capable of sophisticated interdependent joint activity with the human wearer. Under this approach, a tacit adaptability is provided to modulate the compliance in the robot torque controller, to automatically modulate in turn the difficulty of the task [66].
\nThere is currently no agreement on the optimal robot-mediated treatment programs to induce plasticity and promote recovery of motor function following SCI, and the understanding of recovery mechanisms is still an open matter [67]. Whatever the robot hardware and patient’s functional status, a WR-mediated neurorehabilitation model could pave the way for effective restoration of mobility after major neurological conditions. In the last few years, the development of computational neurorehabilitation models is becoming a relevant topic in the domain of neural repair, as these computational models can be expected to provide the basis for future clinical robot software that suggests timing, dosage, and content of therapy. For example, an analytical modeling approach has been applied to robot-mediated rehabilitation data of a group of SCI subjects, providing insights with regard to patient grouping and gait recovery prognosis and also providing predictive quantitative measures to consider before starting the treatment [68]. This, together with the fact that in the past years we are witnessing an unprecedented number of wearable interactive robotics products that will populate even more the clinic environments, a reasonable long-term vision is to gather multicenter clinical data to equip rehabilitation WRs with computational neurorehabilitation modeling tools that will in turn provide enriched data to establish scientific bases of exoskeleton-guided recovery.
\nOn the other hand, the combination of FES with external orthotic devices that provide joint support and mechanical constraint to undesired movements was early proposed [69], but the challenges associated with the rapid onset of muscle fatigue and movement control still remained. In an attempt to further diminish the energy demand from the muscle while providing better joint control, FES systems were combined with lower limb exoskeletons, also called hybrid exoskeletons [70]. The combination of the lower limb robotic exoskeleton and the FES system can be shaped in different ways, depending on the configuration of the FES system and/or the exoskeleton. Regarding the former, the FES can be implanted [71] or superficial [72] and can be found either under open [71, 73] or closed-loop [72, 74] control of stimulation. With regards to the exoskeleton joints, it can provide means of dissipating energy, via the use of clutches or brakes [75, 76], or can feature active joints, which can also provide energy to the joints.
\nThe hybrid configuration presents some advantages with respect to the FES or exoskeleton applications alone. First, the exoskeleton structure provides passive control to the joints, constraining undesirable movements. The actuators can provide support to the joints, diminishing or eliminating the need for stimulation of certain muscles (e.g., quadriceps muscles during the stance phases of walking). In the case of active actuators, the movement produced by the FES is supported by the actuator, improving the control of the joint trajectory while delaying muscle fatigue [77]. On the other hand, the sensors of the exoskeleton provide information for closing the control loop of the FES system, which may further help on optimizing the performance of the muscle in terms of either force production or muscle fatigue [72].
\nDespite hybrid exoskeletons show several advantages, the field is not mature. There is a markedly low activity in this field, and most of the groups working on this technology have discontinued their research on this topic. The rationale for this may come from the bottlenecks of each technology. First, hybrid exoskeletons share drawbacks with lower limb robotic exoskeletons, in which the combination with a FES system add complexity on the control and wearing aspects. Besides, although alleviated by the exoskeleton, the nonlinear muscle response of the stimulated muscles and the muscle fatigue is not adequately solved yet, and eventually all hybrid exoskeletons still have to be designed to function as conventional robotic exoskeletons once muscle fatigue appears.
\nLastly, there is a need of conducting clinical studies that can demonstrate the benefits of using hybrid exoskeleton with respect to exoskeleton alone that actually justify the extra complexity, cost, and cumbersomeness of the FES system.
\nThis chapter presents an overview of the main effects on motor and functional recovery, as well as spasticity and pain, when using a wide range of noninvasive modalities in the rehabilitation of SCI patients, either in the research or the clinical setting. According to the level of stimulation, these modalities were divided into three different sections: brain, spinal cord, and peripheral stimulation. Regarding the last one, stimulation of the peripheral nervous system can also be combined with external devices that assist and allow repetitive motor training (e.g., hybrid exoskeletons and FES driven cycling).
\nNoninvasive brain stimulation (NIBS) techniques such as rTMS and tDCS have the potential to improve motor function recovery and spasticity after SCI. Moreover, NIBS techniques are safe and relatively easy to administer, presenting infrequent mild effects. Very few studies have investigated motor function after delivery of rTMS on SCI patients. Improvements seem to be present when higher rTMS frequencies are used. On the other hand, the few studies that investigated the effects of rTMS on spasticity in iSCI reported some reduction in the clinical symptoms of spasticity [2]. There are less studies of the application of tDCS in motor function or spasticity than those of rTMS [4], though they all showed improvements in upper or lower limb motor function. Thus, more research is needed to address the full potential and incorporate NIBS techniques into SCI rehabilitation [4].
\nAt the spinal level stimulation, tcSCS has irrupted in the last years as a neurorehabilitation tool in SCI. It overcomes the limitation of invasiveness and costs of epidural stimulation at the expense of poor spatial stimulation resolution. The few evidences suggest that tsSCS alone improves voluntary modulation of lower limb movement [29] and increases motor control enhancement when combined with pharmacology therapy and exoskeletons [26].
\nNoninvasive modalities that deliver different types of surface stimulation at the peripheral level (either alone or combined with cycling or robotic-assisted training, for example) are very appealing and have been applied in SCI rehabilitation. Surface electrical stimulation can modulate afferent and efferent pathways in order to induce corticospinal plasticity. For instance, TENS and FES have reduced spasticity in SCI patients and the effects outlasted up to several hours after treatment, though the two techniques target different nerve groups in order to reduce spasticity: TENS activates afferents that in turn activate inhibitory interneurons that will inhibit the spastic muscle activity; FES induces muscle contraction and is oriented to the spastic muscle [34]. The development of fatigue and discomfort produced by the intensity of stimulation of FES is a drawback for long sessions. Thus, TENS may be appropriate for the beginning of the rehabilitation, while FES may have better effects on those SCI patients presenting spasmodic behavior [34]. On the other hand, BMIs may enhance brain and spinal cord neurorecovery through activity dependent plasticity. Future advances in wireless devices may potentiate the widespread use of BMIs in the clinical setting.
\nFES cycling is another modality that presents direct benefits on muscle strength, as well as cardiovascular and respiratory functions of SCI patients. However, more research on this technique is needed in order to design more efficient, natural, and adaptable stimulation protocols, which will likely improve motor function outcomes during SCI rehabilitation.
\nRobotic devices, such as exoskeletons, are other solutions that have been used for rehabilitation purposed after SCI. These devices can provide intensive, long lasting repetitive task specific training to SCI patients, which is the principle behind motor rehabilitation and beneficial neuroplasticity [78]. These devices have allowed SCI patients to ameliorate their performance in daily life [56]. The hybrid configuration (exoskeleton combined with FES) presents some advantages with respect to the FES or exoskeleton applications alone: actuators can provide support to the joints, diminishing or eliminating the need for stimulation of certain muscles; the sensors of the exoskeleton provide information for closing the control loop of the FES system, which may further help on optimizing the performance of the muscle in terms of either force production or muscle fatigue. However, the field is not mature and there is a need of conducting clinical studies that can demonstrate the benefits of using hybrid exoskeleton with respect to exoskeleton alone that actually justify the extra complexity, cost, and cumbersomeness of the FES system.
\nPart of the current SCI rehabilitation research uses the modalities described in this chapter and has presented promising results including neurorecovery.
\nSome of these modalities are already being widely introduced into the clinical rehabilitation of SCI, such as TENS and FES. However, the actual uptake of technology in the clinical setting, especially for SCI rehabilitation, has been very low [5]. There are still some barriers to the clinical implementation of these techniques. Three of those barriers are the feasibility, appropriateness, and the cost. While the research here described is practical for SCI rehabilitation, some of these techniques are less practicable: they require specialized equipment and knowledge, which make them less feasible [5]. Despite the scientific evidence in favor of these technologies, the expertise required to operate and repair emerging technology is usually not found in the clinical setting, which makes it less appropriate. A third barrier that deserves attention is the economic cost, given the fact that most of the clinical centers cannot afford the maintenance of these technologies. To overcome these barriers, it is essential to develop a proactive dialog between researchers and clinicians in order to properly examine each of the emerging modalities that can maximize the outcomes for each individual that suffered a SCI.
\nThis work was funded by the European Union’s Horizon 2020 research and innovation programme (Project EXTEND—Bidirectional Hyper-Connected Neural System) under grant agreement No 779982 and by the EFOP-3.6.1-16-2016-00004 grant.
\nThe authors declare that this work was conducted in the absence of any commercial or financial relationships that could be considered as a potential conflict of interest.
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